Benzthiazide (3-[Benzylthio) Methyl]-6-Chloro-2H-1,2,4 -Benzothiadiazine-7-Sulfonamide 1,1-Dioxide) is known to be practically insoluble in water. The sodium or potassium salts of this compound are soluble but these aqueous solutions are not sufficiently stable at a pH suitable for the preparation of injections. At much higher pH these solutions are not suitable for intra-muscular injection because they often are accompanied by considerable necrotic reactions at the site of the injection. Previously, injectable benzthiazide was prepared for immediate use by the methods disclosed by U.S. Pat. Nos. 3,361,816 and 3,426,130 (incorporated by reference herein). Those methods use lyophylised unstable solutions which are reconstituted for immediate use. These methods have the disadvantage of requiring reconstitution, that is, they require additional time and care of the nurse, physician, veterinarian, etc. who administers the injection, or require the time of an assistant. Lyophylised solutions are not stable enough to be previously prepared and stored as solutions at room temperature. Typical shelf life of the prepared lyophylised solutions is two to three days under refrigeration, though in some instances life can be 30 to 90 days with refrigeration.
I have prepared stable solutions of benzthiazide which are suitable for parenteral administration of this therapeutically important diuretic, and can also be made suitable for other therapeutic methods of administration, such as syrups for peroral administration. The solutions are stable for up to three years or more at room temperature storage. The solutions eliminate the need for on the spot preparations and the time required thereby. The process for the preparation of a clear, stable aqueous solution of benzthiazide is conducted by dissolving the benzthiazide in an effective amount of a polyalkalene glycol and then diluting the solution with a suitable amount of water. Suitable preservatives, such as benzyl alcohol, may be added with the benzthiazide (or after) if multiple dosage containers are to be prepared and the pH of the solution is adjusted to between about 3 to 6 for injection.
Preferred polyalkalene glycols are the polyethylene glycols, particularly those having an average molecular weight of about 300. However, average molecular weights greater or less than 300 may be effectively used. Any polyalkalene glycol which will dissolve benzthiazide in an aqueous solution may be used.